UNIVERSIDADE DO PORTO M ARTA PEREIRA 3.º CICLO FMUP 2013
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MARTA PEREIRA
TESE DE DOUTORAMENTO APRESENTADA
À FACULDADE DE MEDICINA DA UNIVERSIDADE DO PORTO EM SAÚDE PÚBLICA
IN CORONARY HEART DISEASE
MORTALITY IN PORTUGAL,
1995-2008
MARTA PEREIRA FMUP 2013MARTA PEREIRA
TESE DE DOUTORAMENTO APRESENTADA À FACULDADEDE MEDICINA DA UNIVERSIDADE DO PORTO EM SAÚDE PÚBLICA
EXPLAINING THE DECLINE
IN CORONARY HEART DISEASE
MORTALITY IN PORTUGAL,
1995-2008
TESE DE DOUTORAMENTOAPRESENTADA À FACULDADE DE MEDICINA DA UNIVERSIDADE DO PORTO
Professores Catedráticos Efectivos
Doutor Manuel Alberto Coimbra Sobrinho Simões Doutor Jorge Manuel Mergulhão Castro Tavares Doutora Maria Amélia Duarte Ferreira
Doutor José Agostinho Marques Lopes
Doutor Patrício Manuel Vieira Araújo Soares Silva Doutor Daniel Filipe Lima Moura
Doutor Alberto Manuel Barros da Silva
Doutor José Manuel Lopes Teixeira Amarante Doutor José Henrique Dias Pinto de Barros
Doutora Maria Fátima Machado Henriques Carneiro Doutora Isabel Maria Amorim Pereira Ramos
Doutora Deolinda Maria Valente Alves Lima Teixeira Doutora Maria Dulce Cordeiro Madeira
Doutor Altamiro Manuel Rodrigues Costa Pereira Doutor Rui Manuel Almeida Mota Cardoso Doutor António Carlos Freitas Ribeiro Saraiva Doutor José Carlos Neves da Cunha Areias
Doutor Manuel Jesus Falcão Pestana Vasconcelos
Doutor João Francisco Montenegro Andrade Lima Bernardes Doutora Maria Leonor Martins Soares David
Doutor Rui Manuel Lopes Nunes
Doutor José Eduardo Torres Eckenroth Guimarães Doutor Francisco Fernando Rocha Gonçalves Doutor José Manuel Pereira Dias de Castro Lopes Doutor Joaquim Adelino Correia Ferreira Leite Moreira Doutora Raquel Ângela Silva Soares Lino
Doutor Abel Vitorino Trigo Cabral
Doutor Alexandre Alberto Guerra Sousa Pinto Doutor Álvaro Jerónimo Leal Machado de Aguiar Doutor Amândio Gomes Sampaio Tavares
Doutor António Augusto Lopes Vaz
Doutor António Carvalho Almeida Coimbra Doutor António Fernandes da Fonseca
Doutor António Fernandes Oliveira Barbosa Ribeiro Braga Doutor António Germano Pina Silva Leal
Doutor António José Pacheco Palha
Doutor António Luís Tomé da Rocha Ribeiro
Doutor António Manuel Sampaio de Araújo Teixeira Doutor Belmiro dos Santos Patrício
Doutor Cândido Alves Hipólito Reis
Doutor Carlos Rodrigo Magalhães Ramalhão Doutor Cassiano Pena de Abreu e Lima Doutor Daniel Santos Pinto Serrão
Doutor Eduardo Jorge Cunha Rodrigues Pereira
Doutor Fernando de Carvalho Cerqueira Magro Ferreira Doutor Fernando Tavarela Veloso
Doutor Francisco de Sousa Lé
Doutor Henrique José Ferreira Gonçalves Lecour de Menezes Doutor José Augusto Fleming Torrinha
Doutor José Carvalho de Oliveira
Doutor José Fernando Barros Castro Correia Doutor José Luís Medina Vieira
Doutor José Manuel Costa Mesquita Guimarães Doutor Levi Eugénio Ribeiro Guerra
Doutor Luís Alberto Martins Gomes de Almeida Doutor Manuel António Caldeira Pais Clemente Doutor Manuel Augusto Cardoso de Oliveira Doutor Manuel Machado Rodrigues Gomes Doutor Manuel Maria Paula Barbosa
Doutora Maria da Conceição Fernandes Marques Magalhães Doutora Maria Isabel Amorim de Azevedo
Doutor Mário José Cerqueira Gomes Braga Doutor Serafim Correia Pinto Guimarães
Doutor Valdemar Miguel Botelho dos Santos Cardoso Doutor Walter Friedrich Alfred Osswald
Doutor José Agostinho Marques Lopes (Presidente) Faculdade de Medicina da Universidade do Porto Doutor Lino Manuel Martins Gonçalves
Faculdade de Medicina da Universidade de Coimbra Doutor Pedro Manuel Marques Vidal
Institut Universitaire de Médecine Sociale et Préventive, Lausanne Doutora Ana Azevedo Cardoso de Oliveira (Orientador)
Faculdade de Medicina da Universidade do Porto Doutor José Henrique Dias Pinto de Barros Faculdade de Medicina da Universidade do Porto Doutora Maria Júlia Pires Maciel Barbosa
Faculdade de Medicina da Universidade do Porto Doutora Raquel Lucas Calado Ferreira
I. Pereira M, Peleteiro B, Capewell S, Bennett K, Azevedo A, Lunet N. Changing patterns of cardiovascular diseases and cancer mortality in Portugal, 1980-2010. BMC Public Health. 2012;29(1):1126.
II. Pereira M, Carreira H, Vales C, Rocha V, Azevedo A, Lunet N. Trends in hyper-tension prevalence (1990-2005) and mean blood pressure (1975-2005) in Portugal: a systematic review. Blood Press. 2012;21(4):220-6.
III. Pereira M, Carreira H, Lunet N, Azevedo A. Trends in prevalence of diabe-tes mellitus and mean fasting glucose in Portugal (1987-2009): a systematic review. [submetido]
IV. Pereira M, Lopes-Conceição L, Bennett K, Dias P, Lunet N, Azevedo A. Trends in pharmacological therapy following an acute coronary syndrome in Portugal: a systematic review. J Cardiovasc Med. 2013; in press.
V. Pereira M, Araújo C, Dias P, Lunet N, Subirana I, Marrugat J, Capewell S, Bennett K, Azevedo A. Age and sex inequalities in the prescription of evidence-based pharmacological therapy following an acute coronary syndrome in Portugal: the EURHOBOP study. Eur J Prev Cardiol. 2013; in press.
VI. Pereira M, Azevedo A, Lunet N, Carreira H, O’Flaherty M, Capewell S, Bennett K. Explaining the decline in coronary heart disease mortality in Portugal between 1995 and 2008. [submetido]
Ao longo desta dissertação, colaborei na definição das hipóteses em estudo e dos objetivos a responder em cada um dos artigos, bem como na análise estatística dos dados. Fui responsável pela redação da versão inicial de todos os manuscri-tos e colaborei ativamente na preparação das suas versões finais.
tação do Professora Doutora Ana Azevedo (Faculdade de Medicina e Instituto de Saúde Pública da Universidade do Porto) e co-orientação do Professora Doutora Kathleen Bennett (Department of Pharmacology and Therapeutics, Trinity Centre for Health Sciences, St James’s Hospital, Dublin, Ireland).
Esta investigação foi financiada pela Fundação para a Ciência e a Tecnologia, através de projeto institucional [PIC/IC/83006/2007] e da atribuição de uma bolsa de doutoramento individual [SFRH/BD/46703/2008], co-financiada pelo Programa Operacional Potencial Humano (POPH).
ACS – acute coronary syndrome AMI – acute myocardial infarction ARB – angiotensin receptor blocker CABG – coronary artery bypass graft CHD – coronary heart disease
CVD – cardiovascular diseases DALYs – disability-adjusted life years DPPs – deaths prevented or postponed ECG – electrocardiogram
LDL – low-density lipoprotein LV – left ventricular
NSTE-ACS – non-ST elevation acute coronary syndrome NSTEMI – non-ST elevation myocardial infarction
PCI – percutaneous coronary intervention SCORE – systematic coronary risk evaluation
STEMI – ST segment elevation myocardial infarction WHO – World Health Organization
ter tornado este trabalho uma realidade, contribuindo de uma forma decisiva para o meu crescimento pessoal. Agradeço também toda a amizade e paciência. To Professor Kathleen Bennett I thank all the scientific support and also for wel-coming me to Dublin.
Ao Professor Doutor Henrique Barros, por me dar a conhecer o mundo da Epidemiologia e por ter erguido esta grande escola chamada ISPUP. Agradeço também a confiança que depositou e continua a depositar em mim.
Ao Professor Doutor Nuno Lunet, agradeço a disponibilidade e o importante contributo no conteúdo desta dissertação.
À Helena Carreira agradeço o enorme contributo científico neste percurso e por se ter tornado minha AMIGA.
To Professor Simon Capewell and Martin O’Flaherty and rest of their team, I thank all the work in the development of the IMPACT model.
À Barbara Peleteiro, Elisabete Alves, Joana Bastos, Sílvia Fraga, Raquel Lucas e Sofia Correia por estarem sempre ao meu lado durante este percurso.
À Helena Carreira, Luísa Conceição, Ricardo Soares e Ana Bastos, pela sua ded-icação a tarefas indispensáveis à realização deste trabalho. E por, juntamente com a Barbara Peleteiro, Elisabete Alves, Sara Lourenço, Ana Henriques e Joana Ferreira serem a minha companhia diária e por terem partilhado comigo momen-tos tão especiais.
À Professora Doutora Carla Lopes, por me ter acompanhado nessa experiencia fantástica, paralela a este doutoramento, que foi a organização do Congresso Europeu de Epidemiologia.
À Dra. Paula Dias que mostrou sempre a maior disponibilidade e vontade de partilhar o seu extenso conhecimento clínico e científico.
A todos os co-autores dos artigos que constituem esta tese, pelo seu decisivo contributo.
A todos os colegas do Departamento de Epidemiologia Clínica, Medicina Preventiva e Saúde Pública e do ISPUP, pelo companheirismo e bom ambiente de trabalho.
Aos meus pais, ao António e ao António Pedro agradeço o amor e apoio incondi-cional. E a toda a minha família que me apoiou nos momentos mais difíceis. Ao meu avô, por ter sido um exemplo de vida.
Ao Chapouto, pela paciência, amor e carinho. E agradeço a sua existência porque sem ele…nada disto teria sido possível!!!
to human intellect and enterprise to apply that knowledge creatively and cost-ef-fectively to minimize the future burdens of CVD in all regions of the globe.
Policies and public health interventions are expected to be evidence-based, meaning that they must rely on adequate available data supporting their need and cost-effectiveness. Therefore, along with the population data necessary for decision making, scientific research must be directed at understanding the causes of disease, evaluating prevention, and monitoring the impact of interven-tions to control them.
Coronary heart disease (CHD) mortality has been decreasing in Portugal since the 1980s, like in most developed countries. However, the reasons for this decline are not clear and authors diverge about the main causes for this decline in other countries. Therefore, we aimed to contribute to a better understanding of the epidemiology of CHD in Portugal, in the last few decades. To accomplish this objective, six studies were performed following different designs. The next para-graphs briefly describe the specific objective pursued in each study, as well as the methodology adopted and main results.
1. To describe time trends in mortality rates, absolute number of deaths and years of life lost from cardiovascular diseases and cancer (Paper I)
We estimated the annual percent change in age-standardized mortality rates from cardiovascular diseases and cancer, in each sex. The specific contribution of demographic changes (due to variations in population size and age structure) and the variation in the age-independent “risk” of dying from the disease to the observed trends in the number of deaths was quantified using the tool RiskDiff. Years of life lost were computed using the Global Burden of Disease method. Among men, the mortality rate from all cardiovascular diseases was more than two-fold higher than cancer mortality in 1980. However, three decades later mor-tality from cancer surpassed cardiovascular diseases. After 2005, the years of life lost from cancer were also higher than from cardiovascular diseases. Among women, despite the decrease in death rates, cardiovascular diseases remained the leading cause of death in 2010 and their absolute burden was higher than that of cancers across the whole period, mainly due to more events in older women. 2. To critically summarize the evidence from studies providing data on the dis-tribution of risk factors in adults, in order to analyze time trends in:
a) Hypertension and blood pressure (Paper II)
b) Diabetes mellitus and fasting blood glucose (Paper III)
A comprehensive systematic review was performed, using Pubmed. Reference screening and data extraction were conducted independently by two research-ers. We extracted age and sex specific estimates from the original studies when-ever available. Linear regression models with survey year, participants’ age and significant interaction terms as independent variables, were used to predict eco-logical estimates of the outcomes. For hypertension prevalence and mean blood
Between 1990 and 2005, the prevalence of hypertension defined as blood
pres-sure ≥140/90 mmHg and/or drug treatment remained approximately constant in
young adults and decreased in middle-aged and older adults, whereas the pre-valence of self-reported hypertension increased 0.4% per year overall. Between 1975 and 2005, mean systolic and diastolic blood pressures decreased in mid-dle-aged and older adults, reaching a 32-mmHg decrease in systolic blood pres-sure among women at average age 70.
Time trends of objectively defined diabetes could not be quantified due to the heterogeneity of the diagnostic criteria. Between 1987 and 2009, the prevalence of self-reported diabetes remained approximately constant in young adults, while it increased in middle-aged and older adults, more than two-fold among women and three-fold among men. In the same period, mean fasting glucose increased 7 mg/dL among women and 8 mg/dL among men.
3. To critically summarize the evidence from studies that provide data on the use of pharmacological therapy for secondary prevention, during hospitaliza-tion and prescribed at hospital discharge, following an acute coronary syn-drome (ACS), in order to analyze time trends (Paper IV)
We searched PubMed, to identify studies reporting the proportion of ACS patients treated with aspirin, clopidogrel, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors and statins. We used linear regression to quantify the annual variation in use of drugs, adjusting for the proportion of men in the sam-ple and patients’ mean age, and including a quadratic term of data collection year when relevant.
In 25 eligible studies, including patients treated from 1993 to 2009, we observed an increase in the prescription of pharmacological treatments at hospital dis-charge. Extrapolating from these data, and assuming a mean patient age of 65 years and 70% of men, we estimate that, in 2008, 95% of patients would have been discharged with aspirin, 92% with clopidogrel, 82% with beta-blockers, 80% with ACE inhibitors and 91% with statins. Treatment during hospitalization fol-lowed a similar pattern, except for a steeper increase in ACE inhibitors use, which was initially lower, but reached similar levels to those at discharge in recent years. 4. To analyze the proportion of patients receiving pharmacological therapy as secondary prevention after an ACS admission in a large sample of patients con-secutively discharged from ten Portuguese hospitals, and to explore potential age- and sex-differences (Paper V)
We studied 747 episodes of ST segment elevation myocardial infarction (STEMI) and 1364 of non-ST segment elevation ACS (NSTE-ACS), within a sample of ACS cases consecutively discharged from ten Portuguese hospitals, in 2008-2009. We estimated adjusted odds ratios (OR) for the association of age and sex and the use of each pharmacological treatment.
(ARBs) 82% and 80%, statins 93% and 90%, 3-drug (aspirin / clopidogrel + beta-blocker + statin) 76% and 69% and 5-drug treatment (aspirin + clopidogrel + beta-blocker + ACE-inhibitor / ARB + statin) 61% and 48%, respectively. Among STEMI patients, those aged ≥80 years were substantially less often discharged with clopidogrel [odds ratio (OR)=0.22, 95% confidence interval (95%CI): 0.08-0.56], aspirin + clopidogrel (OR=0.34, 95%CI: 0.15-0.76), beta-blockers (OR=0.39, 95%CI: 0.18-0.82), 3-drug (OR=0.41, 95%CI: 0.21-0.83) and 5-drug treatments (OR=0.44, 95%CI: 0.23-0.83) than those <60 years; women were less likely to be discharged with aspirin + clopidogrel (OR=0.52, 95%CI: 0.29-0.91). Among NSTE-ACS patients, those aged ≥80 years were much less likely to be discharged with beta-blockers (OR=0.58, 95%CI: 0.36-0.93), statins (OR=0.35, 95%CI: 0.19-0.64) and 3-drug treatment (OR=0.47, 95%CI: 0.30-0.75); sex had no significant independent effect on treatment prescription.
5. To model the decline in CHD mortality, quantifying the contribution of changes in the use of evidence-based medical and surgical treatments, and in major cardiovascular risk factors (Paper VI)
The IMPACT mortality model was used to integrate data on trends in uptake of treatments and exposure to risk factors to explain the variation in CHD mortality. Between 1995 and 2008, CHD mortality rates in Portugal decreased by 29% in men and 21% in women aged 25-84 years, corresponding to 3760 fewer deaths in 2008 than expected if 1995 mortality rates had persisted. Approximately 92% of the estimated decrease in number of deaths could be explained by the model; the remaining 8% were attributed to changes in unmeasured factors. Approximately 50% of the decrease explained by the model was attributable to increased uptake of treatments, mainly anti-hypertensive medication (12%) and initial treatments after an acute myocardial infarction (10%), and 42% to population risk factor reductions, mainly blood pressure (27% in men and 60% in women), total cholesterol (14% in men and 5% in women) and smoking in men (11%). However, these reductions were partially offset by adverse trends in dia-betes (18% in men and 2% in women), obesity (6% in men and 5% in women), and smoking in women (2%).
This thesis helped to clarify the contribution of primary and secondary CHD pre-vention to mortality trends in Portugal. The high treatment uptake after disease suggests that the quality of health care in CHD secondary prevention is good. Healthier lifestyles have the potential to be further implemented, particularly since some of the observed decline in main risk factors was due to pharmacolog-ical treatment. This thesis supports the need for a greater investment in primary prevention, mainly through whole population strategies, while it also provides objective evidence for the importance of medical treatments, particularly to fight against age-related inequalities.
As políticas de saúde e intervenções em saúde pública devem basear-se em evi-dência adequada das necessidades das populações e do custo-benefício dessas medidas. Assim, além da colheita e disponibilização de dados da população, é necessária investigação científica dirigida à compreensão das causas de doença, avaliação das medidas preventivas, e monitorização do impacto das interven-ções para a melhoria do estado de saúde.
A mortalidade por doença coronária tem diminuído em Portugal desde os anos 1980, à semelhança da maioria dos países desenvolvidos. No entanto, as razões para este decréscimo não são ainda claras, e diferentes autores têm debatido as suas principais causas noutros países. Desde modo, foi nosso objetivo contri-buir para um melhor conhecimento da epidemiologia da doença coronária em Portugal nas últimas décadas. Neste sentido, foram desenhados seis estudos dis-tintos, cuja metodologia e principais resultados se descrevem abaixo.
1. Descrever tendências temporais na taxa de mortalidade, número de óbitos e anos de vida perdidos por doença cardiovascular e cancro (Artigo I)
Estimámos a variação percentual anual da taxa de mortalidade por doença car-diovascular e cancro padronizada para a idade em cada sexo. A contribuição específica das variações demográficas (devidas à variação do tamanho e estru-tura etária da população) e da variação no “risco” de morte independentemente da idade para a tendência temporal no número de óbitos foi quantificada usando a ferramenta RiskDiff. O número de anos de vida perdidos foi calculado usando o método do estudo Global Burden of Disease.
Nos homens, a taxa de mortalidade por doença cardiovascular foi mais do que duas vezes superior à mortalidade por cancro em 1980. No entanto, três décadas mais tarde esta tendência inverteu-se. Depois de 2005, o número de anos de vida perdidos por cancro foi também superior aos anos de vida perdidos por doença cardiovascular. Nas mulheres, apesar da diminuição na taxa de mortalidade, as doenças cardiovasculares mantiveram-se como principal causa de morte em 2010, e a carga absoluta de doença foi superior à de cancro durante todo o período do estudo, sobretudo devido ao número de ocorrências em mulheres mais velhas.
2. Sumariar de forma crítica a evidência de estudos com dados de distribuição de fatores de risco em adultos, para analisar tendências temporais em:
a) Hipertensão e pressão arterial (Artigo II)
b) Diabetes mellitus e glicemia em jejum (Artigo III)
Foi feita uma revisão sistemática na Pubmed. A identificação das referências relevantes e a extração dos dados foi realizada por dois investigadores de forma independente. Sempre que possível, foram extraídas estimativas específicas
calcular estimativas ecológicas ajustadas dos níveis médios de pressão arterial e glicemia em jejum e da prevalência de hipertensão arterial e diabetes. No caso da prevalência de hipertensão e pressão arterial média, os modelos foram ajustados para o sexo, enquanto que para a prevalência de diabetes e glicémia em jejum os modelos foram estratificados por sexo.
Entre 1990 e 2005, a prevalência de hipertensão definida como pressão arterial ≥140/90 mmHg e/ou com tratamento farmacológico manteve-se aproximada-mente constante nos jovens adultos e diminuiu em adultos de meia idade e ido-sos, enquanto que a prevalência de hipertensão auto-declarada aumentou 0,4% por ano. Entre 1975 e 2005, a pressão sistólica e diastólica média diminuíram nos adultos de meia idade e idosos, atingindo uma diminuição de 32 mmHg na pressão sistólica em mulheres com idade média de 70 anos.
A tendência temporal da diabetes definida com base em medições objetivas não foi quantificável devido à heterogeneidade dos critérios de diagnóstico uti-lizados nos diferentes estudos. Entre 1987 e 2009, a prevalência de diabetes auto-declarada manteve-se aproximadamente constante nos jovens adultos, aumentando no entanto em adultos de meia idade e idosos, mais de duas vezes nas mulheres e três vezes nos homens. No mesmo período, a glicemia em jejum média aumentou 7 mg/dL nas mulheres, e 8 mg/dL nos homens.
3. Sumariar de forma crítica a evidência de estudos com dados de utilização de terapêutica farmacológica como prevenção secundária, durante a hospitali-zação e prescrita à data de alta, no seguimento de síndrome coronária aguda, para analisar tendências temporais (Artigo IV)
Foi realizada uma pesquisa na PubMed para identificar estudos que reportassem a proporção de doentes após síndrome coronária aguda tratados com aspirina, clopidogrel, bloqueadores beta e inibidores da enzima de conversão da angio-tensina (IECAs) e estatinas. Foi utilizada uma regressão linear para quantificar a variação anual na utilização de fármacos, ajustando para a proporção de homens na amostra e idade média dos pacientes, e incluindo um termo quadrático do ano da colheita dos dados, quando relevante.
Em 25 estudos elegíveis, incluindo doentes tratados entre 1993 e 2009, obser-vou-se um aumento da prescrição de terapêutica farmacológica aquando da alta. Destes dados, foi estimado por extrapolação que, aquando da alta, em 2008, a 95% dos doentes foi prescrita aspirina, a 82% bloqueadores beta, a 80% IECAs e a 91% estatinas, assumindo uma idade média dos doentes de 65 anos e 70% de homens na amostra. O tratamento durante a hospitalização seguiu um padrão semelhante, com exceção de um aumento mais acentuado na administração de IECAs, que foi inicialmente mais baixo mas atingiu um nível semelhante ao pres-crito na alta nos últimos anos.
portugueses, e explorar potenciais diferenças por idade e sexo (Artigo V) Numa amostra de casos de síndrome coronária aguda com alta hospitalar em 10 hospitais portugueses admitidos consecutivamente, foram estudados 747 episó-dios de enfarte agudo do miocárdio com elevação do segmento ST (EAMEST) e 1364 de síndrome coronária aguda sem elevação do segmento ST (SCASEST). A proporção de doentes com EAMEST e SCASEST que tiveram alta hospitalar com prescrição de aspirina foi 96% e 88%, com clopidogrel 91% e 78%, com aspi-rina + clopidogrel 88% e 71%, com bloqueadores beta 80% e 76%, com IECAs ou antagonistas do recetor da angiotensina II (ARA II) 82% e 80%, com estatinas 93% e 90%, com terapia tripla (aspirina / clopidogrel + bloqueador beta + esta-tina) 76% e 69%, e terapia quíntupla (aspirina + clopidogrel + bloqueador beta + IECA / ARA II + estatina) 61% e 48%, respetivamente. À data de alta, os doen-tes com EAMEST e idade superior a 80 anos tiveram menos frequentemente prescrição de clopidogrel [odds ratio (OR)=0,22, intervalo de confiança a 95% (IC a 95%): 0,08-0,56], aspirina + clopidogrel (OR=0,34, IC a 95%: 0,15-0,76), bloqueadores beta (OR=0,39, IC a 95%: 0,18-0,82), terapia tripla (OR=0,41, IC a 95%: 0,21-0,83) e terapia quíntupla (OR=0,44, IC a 95%: 0,23-0,83) quando comparados com os doentes com idade inferior a 60 anos; no momento da alta médica, às mulheres foi menos frequentemente prescrita a associação aspirina + clopidogrel (OR=0,52, IC a 95%: 0,29-0,91). Nos doentes com SCASEST com mais de 80 anos, foram prescritos menos frequentemente bloqueadores beta (OR=0,58, IC a 95%: 0,36-0,93), estatinas (OR=0,35, IC a 95%: 0,19-0,64) e tera-pia tripla (OR=0,47, IC a 95%: 0,30-0,75); o sexo não teve efeito significativo independente no tratamento prescrito.
5. Modelar o decréscimo na mortalidade por doença coronária, quantificando a contribuição das alterações na utilização de terapêuticas médicas e cirúrgicas baseadas na evidência e nos principais fatores de risco cardiovascular (Artigo VI) Foi utilizado o modelo IMPACT para integrar os dados de tendências de utiliza-ção de tratamentos e exposiutiliza-ção a fatores de risco para explicar a variautiliza-ção na mortalidade por doença coronária.
Entre 1995 e 2008, a taxa de mortalidade por doença coronária em Portugal diminuiu cerca de 29% nos homens e 21% nas mulheres com idades compreen-didas entre os 25 e os 84 anos, correspondendo a 3760 menos mortes em 2008 do que seria esperado se as taxas de mortalidade de 1995 se tivessem mantido. Aproximadamente 92% da diminuição do número de mortes estimada foi expli-cada por este modelo; os restantes 8% são atribuíveis a alterações em fatores não considerados. Cerca de 50% da diminuição explicada por este modelo foi atribuída ao aumento da utilização de tratamentos, sobretudo anti-hipertensores (12%) e ao tratamento inicial após enfarte agudo do miocárdio (10%), e 42% a redução de fatores de risco na população, principalmente pressão arterial (27% nos homens e 60% nas mulheres), colesterol total (14% nos homens e 5% nas mulheres) e consumo de tabaco nos homens (11%). No entanto, estas reduções
Este trabalho ajudou a clarificar a contribuição da prevenção primária e secun-dária para a tendência da mortalidade em Portugal por doença coronária. A ele-vada utilização de tratamentos médico-cirúrgicos após a doença sugere que a qualidade dos cuidados de saúde na prevenção secundária de doença coroná-ria é boa. Os estilos de vida mais saudáveis deverão ser mais implementados, nomeadamente dado que grande parte do decréscimo observado nos principais fatores de risco foi devida a tratamento farmacológico. Esta tese apoia a neces-sidade de um maior investimento na prevenção primária, principalmente atra-vés de estratégias de base populacional, fornecendo também evidência objetiva relativamente à importância dos tratamentos médicos, em particular no combate a desigualdades relacionadas com a idade.
The common occurrence of cardiovascular diseases (CVD) in most populations and their impact on mortality, loss of independence, impaired quality of life, and social and economical costs are compelling reasons for public health concern. Policies and public health interventions are expected to be evidence-based, meaning that they must rely on adequate available data supporting their need and cost-effectiveness. Therefore, along with collecting and allowing access to the population data necessary for decision making, scientific research must be directed at understanding the causes of disease, evaluating prevention, and monitoring the impact of interventions to control them.
1.1 Atherosclerosis
Atherosclerosis is a pathological condition that occurs in the inner lining of medium and large arteries throughout the body. It consists on a chronic inflam-matory process, which develops over decades in response to the biologic effects of risk factors 1, 2. Atherosclerosis affects especially the heart, aorta, brain and lower extremities.
Figure 1 describes schematically the development of an atherosclerotic lesion. The process starts with changes in endothelial permeability and in the compo-sition of the extracellular matrix below the endothelium that promote the entry and retention of cholesterol-containing low-density lipoprotein (LDL) particles in the artery wall 3. The induction of endothelial and smooth cell activation, secre-tion of inflammatory mediators and expression of adhesion molecules leads to leukocyte accumulation in the sub-endothelium. This inflammatory response in turn can promote further oxidation of the LDL particles, resulting in the activa-tion of macrophages that engulf the LDL particles to become “foam cells” (cells loaded with lipids). These activated macrophages can then further contribute to damage by various secreted mediators or by adding thrombogenic and anti-genic debris to the lesion, fostering the progress of the resulting atheroscle-rotic plaque 4. The fracture of the plaque’s fibrous cap enables blood coagulation components to come into contact with tissue factors in the interior of the plaque and can result in the occlusion of the artery and consequent symptoms due to impaired or obstructed blood flow to the tissues beyond 5.
The risk factors for atherosclerosis act at several points of this pathogenic path-way 1, 2. A change in the integrity of the endothelial cells is responsible for the beginning of the whole process. This could be initiated by oxidative, hemody-namic, or biochemical stimuli (from smoking, hypertension, or dyslipidemia) and inflammatory factors, that change their permeability to promote the entry and retention of blood monocytes and LDL particles. Hypertension is a major risk factor for atheromata, and can increase arterial wall tension, leading to disturbed repair processes and aneurysm formation. Cigarette smoking and diabetes
mel-litus also affect vascular biology, but through less well understood biochemical
mechanisms. The evidence that supports the causal role of LDL cholesterol in atherosclerosis is vast. A strong association between LDL cholesterol and ath-erosclerosis was first observed in ecological studies, then tested in animal mod-els, and confirmed in large epidemiological and intervention studies 6.
1.2. Clinical presentation and natural history of coronary
heart disease
Coronary heart disease (CHD) or ischaemic heart disease comprises many con-ditions that vary widely in manifestations and in public health importance, and together contribute to CVD mortality and morbidity 7. All CHD conditions appear after longstanding disease of the walls of arteries that supply the myocardium. The myocardial cells are dependent on a continuous supply of oxygen and nutri-ents, and if the blood flow is interrupted and not restored within minutes, injury and death take place. The typical symptom is pain due to muscle ischemia, with or without vegetative accompanying symptoms, which subsides or resolves
upon recovery of enough blood flow to meet oxygen needs 8-10.
Figure 2 represents the typical phases in the development of CHD from the per-spective of its biological and clinical progression. After the silent progression
atherosclerotic lesions (reproduced from Libby P et al. 5).
resulting small clot and some enlargement of the plaque may occur. Sometimes a large occlusive clot produces acute events, like unstable angina, myocardial infarction or sudden death. If the acute event does not result in sudden death, other short- or long-term outcomes are possible: recovery, short-term fatality, later recurrence as a new episode or late coronary death. During this process there are several phases when the cascade can be stopped or at least post-poned: by delaying the development of the plaque, avoiding the precipitating factors, or allowing a rapid access to treatments.
Stable angina is chest pain that normally occurs when the demand of blood flow-ing through the heart arteries increases, usually when a person exercises stren-uously 10. Unstable angina and acute myocardial infarction (AMI) are character-ized by a sudden worsening of angina symptoms, which become more frequent, more prolonged, and more severe and/or happen at a lower threshold or at rest. If the blood clot grows to completely obstruct the circulation causing necrosis of the heart muscle, the patient suffers an AMI 8, 9. Furthermore, because one of the main consequences of atherosclerotic obstruction is the loss of myocardial muscle, a common occurrence in many of these patients is the subsequent devel-opment of heart failure, a condition with particularly high mortality, poor quality of life and with high consumption of healthcare resources 10.
Further details about the diagnosis of CHD and risk stratification for treatment decisions will be given in a subsequent subsection about management of CHD.
1.3. Burden of coronary heart disease
Characterizing the distribution of a disease is essential to its epidemiologic under-standing. Descriptive epidemiology aims to study the distribution of disease in relation to persons, place, and time. One tenet of epidemiology is that patterns Figure 2. Development and main outcomes of CHD (adapted from Labarthe DR 11). unstable angina cardiac dysfunction without symptoms stable angina Status of disease
Short –term fatality (≤28 days) Sudden death Symptomatic ischaemia -unstable angina -myocardial infarction Surface disruption or fissure of a plaque/thrombosis Advanced atherosclerotic lesions in the coronary arteries Recovery -Spontaneous resolution/ plaque enlargement Asymptomatic disease/ silent infarction Late recurrence (>28 days)
Late coronary death (>28 days)
Circumstances and time frame
Background conditions (years to decades)
Precipitating factors (seconds to hours)
Intermediate and late developments (days to years) Acute event
The most frequent assessment of the global burden of diseases focuses on mor-tality data, which is often the most readily available health indicator albeit with important and sometimes severe limitations. Some projects, like Global Burden of Diseases Study 7, go beyond mortality data to estimate burdens due to disabil-ity and premature deaths. The Global Burden of Disease Study made it clear that, accompanying the gratifying gains in cardiovascular health that occurred in the industrially developed nations towards the last decade of the twentieth century, there was an alarming escalation of the CVD epidemic in other and more pop-ulous regions of the world. According to this study, CHD was the first cause of death worldwide in 1990 and was projected to remain in this rank 30 years later, in 2020. Years of life lost, the second indicator analyzed, were estimated taking into account predicted ages at death in relation to an assumed life expectancy of 82.5 years. In these computations, CHD was projected to advance from fourth to first rank between 1990 and 2020. In addition, when the years of life lost are combined with years lived with disability a new measure of burden is calculated, the disability-adjusted life years. The position of CHD is expected to move up from fifth to first rank between 1990 and 2020. It is noteworthy that CHD con-tributes importantly to disease burden in terms not only of death but also of reduced life expectancy and disability. CHD is estimated to rank first among all heath conditions in all three measures by 2020, less than a decade from now. The lifetime risk of CHD estimated in the Framingham Heart Study population at age 40 was 48.6% for men and 31.7% for women 13.
In Europe, CHD remains the major cause of death, accounting for 1.8 million deaths each year, and is also a major cause of morbidity and loss of quality of life. Death rates from CHD are generally higher in Central and Eastern Europe than in
Northern, Southern and Western Europe 14. Apart from being different, the CHD
mortality rates trends decreased in most European countries, in the last 30years
15. Figure 3 depicted the percent changes in CHD mortality in some European
countries in between 1990 and 2010.
Figure 3.
Percent change is CHD mortality rates, in adults under 65 years, by sex, 1990-2010, in some European countries (data source WHO 16)
-34 -35 -24 -37 -42 -63 -82 -88 37 -29 -33 -50 -40 -40 -57 -73 -78 39 -170 -70 30 United Kingdom Finland Italy Sweden Portugal Spain Croatia Romania Ukraine
% change in CHD mortality rates
Men Women
outcome and an increase of life expectancy. The number of patients who survive a cardiovascular event, and who require subsequent medical or interventional therapy is increasing and the burden of CVD has shifted from the middle aged to the elderly, but remains high.
1.4. Major risk factors for coronary heart disease
The study of the physiopathology of CHD made clear that this group of dis-eases is characterized by a long asymptomatic latent period, which provides an opportunity for early preventive interventions that change disease course. In the past half-century, extensive documentation was produced, not only on the occurrence of CHD throughout the world but also reporting the results of successful investigation on its underlying causes and prevention. The vast shifts in causes of death stimulate strong epidemiologic interest because they must reflect profound changes in the factors that influence health and disease17. Strategies of prevention were derived from the concept of “risk factors”, intro-duced in 1961 by researchers of the Framingham Heart Study 18. In 1978, the term “primordial prevention” was proposed by Strasser and introduced in the scientific community 19. From 1981, Rose articulated more clearly the idea of two comple-mentary approaches to shifting adverse population distributions of risk factors towards more favorable ones, by a “high-risk” strategy of intensive intervention targeting those at the extreme of risk and a “mass” or “population-wide” strategy to shift the whole distribution towards lower risk 20. Throughout the years, many factors have been causally related to the development of arterial atherosclerosis,
and the landmark Framingham study identified most of them 21.
The study of the role of CHD risk factors is complex and needs to consider innu-merable connections between characteristics of individuals (e.g. age, sex, genetic inheritance), their lifestyles (e.g. diet, smoking, alcohol), metabolic processes (e.g. lipid metabolism, blood pressure) and also extrinsic social and environmental con-ditions. Due to this complexity, it has been difficult to clearly define which are the major risk factors for CHD. Different authors and institutions have diverged in the criterion used for this selection. In 2004, Stamler and colleagues reviewed the his-tory of research and suggested six established major risk factors: serum total cho-lesterol, blood pressure, cigarette smoking, body mass index, diabetes and adverse diet has a determinant factor for all the others22. The selection of these factors was justified on the basis of their role in the etiology of the disease, their strong impact on risk and their potential for being prevented or reversed 22. The investigators of the INTERHEART study, which included a sample of 15152 AMI cases and 14820 controls from 52 countries, identified nine risk factors which together explain over 90% of the myocardial infarction risk: smoking, dyslipidemia, hypertension, diabe-tes, obesity, unhealthy diet, physical activity, alcohol consumption, and psychoso-cial factors 23. Regardless of the chosen criteria, some risk factors are consistently present in all lists of major risk factors for CHD.
countries income countries Burden (DALYs) Mortality Burden (DALYs) Mortality Burden (DALYs) Mortality High cholesterol 57 52 46 43 48 45
High blood pressure 48 49 44 47 45 47
Overweight and obesity
27 19 16 14 18 15
Smoking 23 15 15 11 17 12
Physical inactivity 21 19 21 20 21 19
DALYs- disability-adjusted life years
The Global Burden of Disease and Risk Factors incorporates a detailed assess-ment of risk factors as well as diseases worldwide and reported estimates of the contribution of selected risk factors to the burden of diseases 24. The results pre-sented in Table 1 are population attributable fractions for each risk factor, and the outcomes represent the percentage of burden measured as disability-adjusted life years and mortality. Each risk factor was considered separately, and since factors frequently concur to disease occurrence, the cumulative percentages for multiple risk factors may exceed 100%. Within the risk factors considered individually, high cholesterol stands out as the leading factor for CHD, followed by high blood pressure. If the high cholesterol distribution of the high income region were reduced to the theoretical minimum risk exposure (defined as bel-low 0.6 mmol/L), the burden of CHD would be expected to be 57% bel-lower, and the mortality would be reduced by 52%. In this study diabetes was considered as a disease and not as a risk factor.
This and other evidence suggests that there is a vast potential for prevention, if public health strategies are implemented and sustained to preserve low risk or restore the more favorable distributions of risk. Once the most important modifiable risks are defined, and since these risk factors together with diabetes account for about 75% of CHD 25, it is crucial to analyse their distribution in the populations.
According to the most recent European Cardiovascular Disease Statistics from the European Society of Cardiology, women are now smoking nearly as much as men, fruit and vegetables consumption has increased in recent decades, while overall fat consumption has remained stable; few adults participate in adequate levels of physical activity, with inactivity more common among women than men; levels of obesity are high across Europe both in adults and children; and the prevalence of diabetes has increased rapidly over the last ten years, by more than 50% in many countries 14.
world and by broad income group (data source Lopez AD et al.24).
There is relatively little comparable international data on the prevalence of major risk factors. Available data in European countries are usually taken from national health surveys and there are limitations about the comparability due to differences in the study designs (sampling methods, age range) and methods (objectively defined or reported information). Figure 4 depicts the prevalence of major risk factors for CHD in six European countries. Compared to Spain, Italy, United Kingdom, Finland and Sweden, Portugal had higher levels of hyperten-sion, diabetes and physical inactivity in recent years 14. Some methodological issues need to be pointed out: the prevalence of hyperlipidemia and hyperten-sion were quantified using the same definition in all countries and the estimates were age-standardized; the height and weight data in Italy was self-reported and there was no data for United Kingdom; and physical inactivity was defined as answering “no” to the question “How often do you exercise or play sport?”. In 2011, a series of systematic reviews were published with the aim of analysing health examination surveys and epidemiological studies with data on cardiovas-cular risk factors, and estimating worldwide trends for each one 26-29. According to this pooled analysis, the mean systolic blood pressure and serum choles-terol decreased in Western Europe, while body mass index and fasting glucose increased, between 1980 and 2010. The trends varied significantly across regions and countries, supporting the need for specific data from each population. Age and sex play an important role in the epidemiology of the atherosclerotic process, and they are considered the most important non-modifiable risk factors by some authors and institutions, like the World Health Organization30, 31. However, differences in disease distribution by these characteristics could reflect underlying social or environmental factors, like social conditions, behavioral patterns or spe-cific exposures. To this extent health patterns by age and sex may be modifiable. For instance, the increase of blood pressure with age has been seen as a natural or inevitable process, but the degree of increase differs widely between and within populations 32. Additionally, there is strong evidence that the old and very old patients would obtain a particularly large absolute benefit from pharmacological treatment in CHD secondary prevention 33, 34. Thus, age can be seen as a marker for other modifiable risk factors, and the degree of its effect can be changed. Mortality rates by CHD present a striking pattern of variation with age (Figure 5). The increase is evident across age groups. Clear patterns are also evident by sex,
0 20 40 Hyperlipidemia, 2008 Hypertension, 2008 Overweight/obesity, 2002-2010 Smoking, 2006 Diabetes, 2006 Physical inactivity, 2009 P re v a len c e ( % ) Portugal Spain Italy United Kingdom Finland Sweden
risk factors for CHD in Portugal, Spain, Italy, United Kingdom, Finland and Sweden (data source Nichols M et al.14)
(e.g. chromosomal, hormonal or reproductive), social (e.g. access to education or different patterns on occupation), cultural, or behavioral (e.g. health informa-tion or use of health services).
From a public health perspective, these distributions of CHD have further impli-cations. For instance, older age groups experience a higher disease burden than others, and such differences can represent inequalities, beyond the simple fact of variation in disease frequency 35. Explicit attention to the groups most affected should be made a priority for society and decision makers. In contrast to what would be expected, sometimes these groups are those who are
under-represented in CHD epidemiological studies 36 and those who are undertreated
in clinical practice 37.
Risk scores for prevention and management
Changes in the overall distribution of risk factors are important to implement effective strategies targeting not only the general population, but also high-risk groups. For that, the identification of the individuals who are at a high risk is essential. A physician may intuitively estimate the patient’s overall cardiovas-cular risk, based on age, sex, tobacco use, visible obesity, blood pressure levels and other simple measurements. However, this clinical judgement would be very imprecise. Therefore, objective risk assessment using risk charts, calculators or computer programs is recommended. Such risk estimation does not exclude the need for clinical judgement as these tools do not incorporate all risk factors for atherosclerotic disease.
The European guidelines on CVD prevention in clinical practice recommend the
utilization of the detailed SCORE charts 39. The SCORE, as many other similar
risk charts, facilitates the estimation of the risk in apparently healthy persons. This tool allows the estimation of 10-year risk of a fatal cardiovascular event
Figure 5
Mortality rates for CHD by age and sex in Europe and Portugal, in 2008 (data source World Health Organization and Official statistics from Portugal 16, 38) 0 50 100 150 200 250 300 350 15-29 30-44 45-59 60-69 70-79 80+ M o rt a li ty r a te (/ 100 000 ) Age group Europe (men) Europe (women) Portugal (men) Portugal (women)
countries for CVD, and for men and women 40. Patients who have had a clinical event, such as an acute coronary syndrome or a stroke, are automatically eligible for intensive risk factor management.
1.5. Management of coronary heart disease
Given the importance of the population-based and high-risk strategies, a combi-nation of both is likely to lead to the greatest benefits and once an individual has developed CVD, his/her risk of developing other CVD event must be minimized. Depending on the patients’ sex, age and clinical presentation, those who survive the acute stage of a cardiovascular event have a 1.5- to 15-fold higher likelihood of suffering a new event or death, compared to the general population 41.
Historical insight
Advances in the prevention, diagnosis, and treatment of CHD have been remark-able since the mid-20th century (Figure 6). The development of coronary
angi-ography in 1958 42 combined with left ventriculography allowed clinicians to
understand the natural history of coronary artery disease. It became the stan-dard diagnostic tool and provided the basis for surgical treatment using coro-nary revascularization techniques. Additionally, the refinement of the open-heart surgery technique, performed for the first time in 1954 42, made emerge the field of invasive treatments in cardiology. Until 1961, patients with AMI who reached the hospital alive were placed in beds located throughout the hospital far from the vigilance by nurses or doctors. At that time, patients were commonly found dead in their beds, presumably from a fatal tachyarrhythmia. Indeed, the risk of
death occurring in the hospital was approximately 30% 43. The development of
coronary care units, providing continuous monitoring of the electrocardiogram, closed-chest cardiac resuscitation, and external defibrillation, reduced in-hospital mortality by a half among patients admitted with AMI 44. Despite major advances in treatment, by the 1970s, in-hospital mortality from AMI was approximately 18% 45. Evidence on the efficacy of different pharmacological treatments for the secondary prevention after an ACS has become available gradually over the 1980s. Aspirin and beta-blockers were the first with proven effectiveness in CHD patients 46, 47. In the early 1990s, the effect of angiotensin-converting-enzyme (ACE) inhibitors for secondary prevention in ACS patients was first described
48, 49. This drug causes the dilation of blood vessels, slowing the progression of
CVD and improving survival rates, mainly among patients with left ventricular dysfunction. In the mid-1990s, several large randomized clinical trials have estab-lished the effectiveness of statins 50 in delaying death and preventing non-fatal coronary events, in the context of secondary prevention. Finally, it was only in the late 1990s that a role for clopidogrel in the management of CHD was established
51. Meanwhile, in 1986, an Italian group showed that intravenous streptokinase
reduced early mortality in patients with AMI, in one of the first cardiac large trials, involving more than 10,000 patients 52. The combination of coronary angioplasty
In the beginning of the twenty-first century, a clear investment was made at a different level of the clinical pathway, to decrease the time between the onset of symptoms and the patient’s arrival at the hospital, in order to maximize the effec-tiveness of treatment. We have moved from a situation in which many patients spent long hours in small local hospitals, contributing to increasing mortality, to the provision of rapid transport to centers with catheterization laboratory. With all these improvements in treatment, in 2004 the crude in-hospital mortality was 4.0% and at 30 days was 5.1% 54, much lower than 30 years before.
Current European guidelines
The main goal of guidelines is to help physicians to make decisions in their daily practice. They summarize and evaluate all available evidence on a particular issue, and assist the physicians in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk-benefit ratio of particular diagnostic or therapeutic
9. A large number of guidelines about CHD have been issued in recent years by
the European Society of Cardiology and, in addition to define new standards of care, the clinical terminology used to classify the type of ACS also has undergone change. In 2000, the American and European cardiology societies adopted a new AMI diagnostic system that included testing for troponin levels, which are much more sensitive to myocardial necrosis than the cardiac enzymes normally used up until then 55, 56. Nowadays, the current international consensus definition states that the term ‘acute myocardial infarction’ should be used when there is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischaemia 57. This new definition increased the number of non-ST elevation myo-cardial infarction (NSTEMI) cases identified by about 30%, mainly due to patients
1950 1960 1970 1980 1990 2000 2010 1954 Open-heart procedure (Gibbon) 1961 Coronary care unit (Julian) 1979 PCI (Grüntzig) 1993 Superiority of primary PCI vs. fibrinolysis (Grines) 1958 Coronary arteriography (Sones) 1982 β-blocker (BHAT trial) 1969 CABG (Favaloro) 1980 Implantable cardioverter– defibrillator (Mirowski) 1986 Fibrinolysis (GISSI study) 1992 ACE inhibitors (Pfeffer) 1994 Statins (4S study) 1988 Aspirin (Young)
ACE – angiotensin-converting-enzyme; CABG – coronary artery bypass graft; PCI – percutaneous coronary intervention
Figure 6. Main scientific advances in acute coronary syndrome treatment.
Acute coronary syndrome
The current guidelines of the European Society of Cardiology divide the rec-ommendations for patients presenting with acute ischaemic symptoms in two: one for STEMI patients and other for NSTEMI and unstable angina patients 8, 9. Therefore, in the initial diagnosis is fundamental to decide the type of treatment that should be provided (Figure 7). The leading symptom of ACS is chest pain lasting for 20 min or more, not responding to nitroglycerine. Some patients pres-ent with less typical symptoms, such as nausea or vomiting, shortness of breath, fatigue, palpitations or syncope. Since the timely diagnosis is fundamental to successful management, ECG monitoring should be initiated as soon as possible in all patients with suspected of an ACS. Blood sampling for serum markers is routinely carried out in the acute phase and the results are even more important if the ECG is inconclusive.
Figure 7 displays a diagram for in-hospital management of the invasive
strat-egies, for patients with and without ST-segment elevation ACS. In addition to
the invasive treatments, in-hospital pharmacological treatment is a very import-ant part of the process of care and usually includes 3 approaches: import- anti-isch-aemic agents, with the objective of decreasing myocardial oxygen demand (by decreasing heart rate, lowering blood pressure, reducing preload, or reducing myocardial contractility) or increase myocardial oxygen supply (by inducing cor-onary vasodilatation); antiplatelet agents, to decrease the platelet aggregation and inhibit thrombus formation; and anticoagulants agents, to inhibit thrombin
Acute coronary syndrome
Persistent ST-elevation ST/T -abnormalities Normal or undetermined ECG
Troponin rise/fall Troponin normal
STEMI NSTEMI Unstable angina
Admission Working diagnosis ECG Biochemistry Diagnosis Primary-PCI capable center
EMS or non primary-PCI capable center
PCI possible <120 min?
Yes No Primary-PCI Rescue -PCI Coronary angiography Preferably <60 min Preferably ≤90 min (≤60 min in early presenters)
Successful fibrinolysis Immediate fibrinolysis Immediate Preferably 3-24h Chest Pain Immediate transfer to PCI center Yes
No Immediate transfer to PCI center
Preferably ≤30 min Invasive approach Urgent PCI Preferably ≤60 min Preferably <24 h PCI or CABG Intermediate risk
(GRACE score <140 and one major risk criterion )
Preferably <72 h
Assessment of patient risk profile (using high risk criteria and/or applying pre-defined risk scores: e.g. GRACE)
Low risk
(GRACE score ≤108)
Intermediate / high risk
(GRACE score >108)
Conservative approach
High risk
(GRACE score >140 or one major risk criterion)
Very high risk (refractory angina, severe heart failure, life - threatening ventricular arrhythmias,
or haemodynamic instability)
Early PCI or CABG
In case of reversible ischaemia
CABG - coronary artery bypass graft; ECG – electrocardiogram; EMS – emergency medical system; GRACE - Global Registry of Acute Coronary Events; NSTEMI – non ST-segment elevation myocardial infarction; PCI – percutaneous coronary intervention; STEMI – ST-segment elevation myocardial infarction. Figure 7.
Diagnosis and in-hospital treatment using invasive
strategies after an ACS (adapted from Steg G et al. and Fox K et al. 8, 9).
tion), hemodynamic status at admission (e.g. hypotension or bradycardia), inva-sive treatments performed (e.g. percutaneous coronary intervention (PCI) with stent) and several other indicators (e.g. risk of bleeding). For instance, STEMI patients undergoing primary PCI should receive a combination of dual antiplate-let therapy with aspirin and an adenosine diphosphate receptor blocker, as early as possible before angiography, and an anticoagulant.
Long-term therapies are important to decrease the risk for new events and prema-ture death. It was estimated that 20% of all patients were re-hospitalized and 18% of men and 23% of women over 40 years of age died during the first year after an ischaemic event 59. Even though long-term management will be mainly the respon-sibility of the general practitioner in a large proportion of patients, these interven-tions will have a higher chance of being implemented if they are initiated during the hospital stay 60. The combination of drug therapies and lifestyle changes need to be considered as fundamental for effective secondary prevention.
The key lifestyle interventions include cessation of smoking, blood pressure con-trol, healthy diet, weight control and the improvement of physical activity. For current smokers, stopping smoking is potentially the most effective of all sec-ondary prevention measures, reducing subsequent CVD mortality by nearly 50% 61. The combination of drug therapy [beta-blockers and ACE-inhibitors or angio-tensin receptor blocker (ARB)] and lifestyle modification (reduced salt intake) may help to achieve the systolic blood pressure between the recommended lev-els after an ACS (≥110 mmHg and <140 mmHg) 62. A healthy diet could help to avoid obesity and decrease blood pressure, and should be based on an a suitable energy intake; increasing the consumption of fruit, vegetables, whole-grain cere-als, fish, lean meat and low-fat dairy products; reducing total fats and salt intake
39. Although it has not been established that weight reduction per se reduces
mortality, the body mass index should be sustained at the optimal levels, below
25 kg/m2, because weight loss can improve many obesity-related risk factors.
The benefits of exercise therapy in the reduction of future cardiac events are well established and are related with improvement of endothelial function and collateralization and reduction of the progression of coronary lesions and the thrombogenic risk. A proper exercise training program could reduce the CVD mortality by 26% 63. A comprehensive, multidisciplinary and structured rehabil-itation program has been shown to be effective in reducing all-cause mortality and the risk of re-infarction, as well as improving risk factors, exercise-based capacity and health-related quality of life after an ACS 64. However, due to the limited number of rehabilitation services, and partly because of a lack of ade-quately trained professionals, only high risk patients, with multiple modifiable risk factors, have access to this reintegration program.
Aspirin Low dose, indefinitely I A I A Clopidogrel For those who are intolerant to
aspirin
I B I A
Dual antiplatelet therapy
Patients with stent I A I A
Patients without stent IIa C I A
Beta-blockers All patients IIa B IIa B
Patients with heart failure or LV dysfunction
I A I A
ACE-inhibitors All patients IIa A I B
Patients with heart failure or LV dysfunction
I A I A
ARB For those who are intolerant to ACE-inhibitors
I B I B
Statins With target LDL-C levels <1.8 mmol/L
IIa C I B
Aldosterone
antagonist Patients with LV dysfunction and either diabetes or heart failure, without significant renal dysfunction
I B I A
ACE – angiotensin-converting-enzyme; ARB – angiotensin receptor blockers; LV – left ventricular; NSTE-ACS – Non-ST elevation acute coronary syndrome; STEMI – ST segment elevation myocardial infarction
The main treatments with proven efficacy in secondary prevention that must be implemented after an ACS are described in Table 2. A patient without contrain-dications should be discharged at least with aspirin, clopidogrel, a beta-blocker, a statin and an ACE-inhibitor or ARB.
Stable angina pectoris
The last guidelines on the management of stable angina pectoris of the European Society of Cardiology were published in 2006 10. The diagnosis of stable angina is mainly based on the patient’s clinical history, and on the presence of chest pain, pressure, or heaviness that limits exertion, situated over the sternum or in the left chest and left arm. It begins gradually after physical or emotional triggers and is relieved within 10 min of rest 10. In the majority of cases, it is possible to make a reliable diagnosis on the basis of the clinical history only, although phys-ical examination and objective tests are necessary to confirm the diagnosis and assess the severity of underlying disease 10. To confirm the diagnosis and plan further management, is recommendable an initial non-invasive strategy, like an exercise ECG, stress echo, or myocardial perfusion scintigraphy. Coronary arte-riography is generally undertaken for further risk stratification purposes. These exams allow the confirmation of the diagnosis, the assessment of the severity of CHD in patients with mild-to-moderate symptoms and the effective risk stratifi-cation. Although stable angina is less severe than an ACS, there is an increased risk of progression to AMI and/or death.
The recommend secondary prevention after a diagnosis of stable CHD is very similar with the recommended after an ACS. In the absence of contraindications or intolerance, patients with stable angina pectoris should be treated with aspirin and statin therapy. A beta-blocker should be used first line or, alternatively, a for each drug
recommended for secondary prevention in STEMI and NSTE-ACS patients (data sources Steg G et al. and Fox K et al. 8, 9).
addition to pharmacological intervention.
Secondary prevention in Europe
As the diagnosis of stable angina in epidemiological studies is mainly based on clinical history and usually the patients are diagnosed in primary care, studies describing secondary prevention on CHD stable patients are rare, and the com-parability between the few exiting is difficult since it dependents on the subjec-tive definition used. Therefore, we are going to focus on the description of the implementation of secondary prevention only among ACS patients.
Despite the recommendations, the implementation of the evidence-based treat-ment after an acute coronary event is far from optimal and rates of surgical procedures and drug treatment vary widely across Europe. To compare data from different countries is usually very difficult because the quality and the rep-resentativeness of data are limited and different from one country to another. However, according to Eurostat, reported in the European Cardiovascular
Disease Statistics 14, among 24 European countries Portugal had the
low-est rates of coronary angioplasty (23 procedures per 100,000 inhabitants in 2009), 20 times less than the country with highest rates, Germany. For coro-nary artery bypass graft (CABG), rates were highest in Germany and Estonia, lowest in Finland and Romania. In Portugal, 40 CABG procedures per 100,000 inhabitants were performed in 2009. However, direct comparisons between the number of procedures performed in each population cannot be interpreted as an indicator of the quality of care without considering the ACS incidence in each country. Portugal is a low risk country for CHD, and the number of patients discharged per year is approximately 3 times lower than in Germany (339 versus 916 patients discharged per 100,000 inhabitants in 2008), so it is understandable that the number of procedures is lower than some high risk countries 16.
Concerning pharmacological treatment, the most comprehensive data is from
the EUROASPIRE project65. This study from the European Society of Cardiology
has collected, among other data, information on drug prescriptions for patients with diagnosed cardiovascular conditions. The first EUROASPIRE survey was performed in 1995–96 in 9 European countries, the second in 1999–2000 in 15, and the third in 2006–07 in 22, including eight countries that participated in EUROASPIRE I and II (Czech Republic, Finland, France, Germany, Hungary, Italy, The Netherlands, Slovenia and Spain). Although these data are not necessarily representative of national prescribing patterns, since in some cases only one region within the country was covered, they give some indication of the scale of drug use across Europe.
The trends in the proportion of drugs prescribed for secondary prevention in CHD patients, in all eight EUROASPIRE populations, between survey I and III, are described in Figure 8. Overall, the proportion of patients treated with antiplatelet increased slightly, but the proportion was already high in 1995–96; on the other hand the proportion of ACE-inhibitors/ARB and statins was three- and four-fold higher in 2006/7 comparing with 1995–96, respectively. There was also a large increase in the prescription of beta-blockers.
Considering the results from the 22 countries included in EUROASPIRE III sur-vey, in 2006/07, the use of pharmacological treatment varied considerably across survey populations. Antiplatelet drugs were the most widely used drugs, between 88% and 99% of patients in the countries studied. Beta blockers were used by more than 60% of patients in all countries (from 60% in Cyprus to 94% in Finland). The use of ACE-inhibitors/ARB varied two-fold, from 46% of patients in Belgium to 90% of patients in Poland. Statins were the treatment with highest variation between countries, from 38% in Lithuania to 96% in Finland. Data from Portugal were not reported in any of the surveys.
1.6. Coronary heart disease policy models
Understanding the trends of a disease is a complex process which involves the quantification of a lot of different factors, most of them susceptible of being influenced by policy decisions. Variations in exposure to risk factors and in the use of medical interventions may have an important effect on disease incidence and case-fatality, and therefore mortality.
Models can be designed to accommodate complexity around the development of an illness in a population. A model is a simplification of reality 66, which starts with some specific data and, based on mathematical equations, can explain past disease trends and predict future events such as disease occurrence 67. Models have been increasingly used in policy making and resource allocation, because they allow the simulation of different scenarios in populations and hence guide future policy decisions 68. They can also help to explore the potential importance of factors on which evidence is sparse or lacking. Modeling complements other epidemiological studies, with advantages in allowing questions to be addressed that traditional research methods do not. The main problem with using models is that they require considerable data input and the data sources need to be CHD treated with
pharmacological therapy for secondary prevention in EUROASPIRE survey populations (data sources EUROASPIRE study 65). 56 31 18 49 57 0 10 20 30 40 50 60 Beta-blockers
Antiplatelet therapy ACE-inhibitors / ARB Statins
P ropo rt ion of pat EUROASPIRE I (1995/96) EUROASPIRE II (1999/00) EUROASPIRE III (2006/07)
prehensive high quality data is the main challenge 69.
A basic cardiovascular model may include levels of the main risk factors, uptake of treatments, demographic information and some outcome measure of CVD, most commonly mortality. In order to explain the CHD mortality trends in the last decades, several models were developed 70. Their main objective has been to understand if the observed trends mainly reflect increasing use of evidence-based treatments for individual patients, or cardiovascular risk factor improvements across entire populations.
The results from the WHO MONICA study suggested that approximately one third of the CHD mortality fall in the mid-1980s/1990s was attributable to the decrease in case-fatality, mainly reflecting treatments, while some two thirds were attributable to fewer events, mainly reflecting prevention through reduc-tions in major risk factors such as smoking, cholesterol and blood pressure 71. More recently, Lopez and colleagues developed the Global Burden of Disease model, which has been valuable for international comparisons, emphasising the powerful contributions from elevated cholesterol, smoking and hypertension 72. However, a more detailed understanding of CHD trends in specific populations combining both risk factors and treatment data and quantified the uncertainties around the model estimates was necessary.
In the last 30 years, several models were developed to explore trends in CHD
73-75. Existing CHD policy models vary widely in their depth, quality, utility and
versatility (Table 3). Some simply consider risk factors alone 72, 74, 75, while others
include selected cardiovascular treatments 76-78. Few models have been
cali-brated against observed data, replicated in different settings or adequately validated.
